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WO2005058911A2 - [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome - Google Patents

[1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome Download PDF

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Publication number
WO2005058911A2
WO2005058911A2 PCT/US2004/041735 US2004041735W WO2005058911A2 WO 2005058911 A2 WO2005058911 A2 WO 2005058911A2 US 2004041735 W US2004041735 W US 2004041735W WO 2005058911 A2 WO2005058911 A2 WO 2005058911A2
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alkyl
substituted
alkoxy
hydroxyl
halogen
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WO2005058911A3 (fr
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Anura P. Dantanarayana
Jesse Albert May
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Alcon Inc
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Alcon Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to the use of substituted [l,4]oxazino[2,3- gjindazols for lowering and controlling normal or elevated intraocular pressure (IOP) and for treating glaucoma.
  • IOP intraocular pressure
  • glaucoma The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve.
  • the several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease.
  • Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated.
  • Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
  • Serotonergic 5-HTIA agonists have been reported as being neuroprotective in animal models and many of these agents have been evaluated for the treatment of acute stroke among other indications. This class of compounds has been mentioned for the treatment of glaucoma (lowering and controlling IOP), see e.g., WO 98/18458
  • 5-HT 1A antagonists are disclosed as being useful for the treatment of glaucoma (elevated IOP) (e.g., WO 92/0338, McLees).
  • DeSai, et al. WO 97/35579
  • Macor, et al. U.S. 5,578,612
  • 5-HT ⁇ and 5-i ⁇ Ake agonists relate to the use of 5-HT ⁇ and 5-i ⁇ Ake agonists for the treatment of glaucoma (elevated IOP).
  • These anti-migraine compounds e.g., sumatriptan and naratriptan and related compounds, are 5-HT 1B ,D,E,F agonists.
  • 5,571,833 relates to tryptamine derivatives that are 5-HT 2 agonists for the treatment of portal hypertension and migraine.
  • U.S. Patent No. 5,874,477 relates to a method for treating malaria using 5-HT 2A /2c agonists.
  • U.S. Patent No. 5,902,815 relates to the use of 5-HT 2A agonists to prevent adverse effects of NMDA receptor hypo-function.
  • WO 98/31354 relates to 5-HT B agonists for the treatment of depression and other CNS conditions.
  • WO 00/12475 relates to indoline derivatives
  • WO 00/12510 and WO 00/44753 relate to certain indole derivatives as 5-HT 2B and 5-HT 2 c receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity.
  • WO 00/35922 relates to certain pyrazino[l,2-a]quinoxaline derivates as 5-HT c agonists for the treatment of obsessive compulsive disorder, depression, eating disorders, and other disorders involving the CNS.
  • WO 00/77002 and WO 00/77010 relate to certain substituted tetracyclic pyrido[4,3-b]indoles as 5-HT 2 c agonists with utility for the treatment of central nervous system disorders including obesity, anxiety, depression, sleep disorders, cephalic pain, and social phobias among others.
  • Agonist response at the 5-HT 2A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT 2 c receptor possible [Psychopharmacology, Vol. 121:357, 1995].
  • U.S. Patent Nos. 5,561,150 and 5,646,173 relate to certain tricyclic pyrazole derivative compounds which are identified as being 5-HT 2 c agonists for the treatment of CNS diseases and are primarily directed to HpophiUc analogs that have a high probability of entering the brain.
  • U.S. Patent No. 6,245,796 and WO 01/83487 relate to tricyclic 5-HT 2 c agonists for the treatment of CNS diseases. All the patents and publications mentioned above and throughout are incorporated in their entirety by reference herein.
  • U.S. Patent 6,518,294 relates to a broadly identified series of aryl and arylalkyl substituted fused tricyclic pyrazoles that includes certain aryl and arylalkyl substituted [l,4]oxazino[2,3- g-]indazols. None of these are specifically identified in the '294 patent, however. The compounds described in the '294 patent are reported to increase intracellular levels of cGMP.
  • a feature of the present invention is to provide novel compounds which are 5- HT 2 agonists.
  • Another feature of the present invention is to provide compounds which have increased chemical stability and which are useful in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.
  • Another feature of the present invention is to provide compounds which provide a desired level of therapeutic activity in lowering and controlhng normal or elevated intraocular pressure and/or treating glaucoma. Additional features and advantages of the present invention will be set forth in part in the description that follows, and in part will be apparent from the description, or maybe learned by practice of the present invention. The objectives and other advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.
  • the present invention relates to a compound having the Formula I:
  • the present invention further relates to pharmaceutical compositions containing at least one compound of Formula I.
  • the present invention further relates to methods to lower and/or control normal or elevated intraocular pressure by administering an effective amount of a composition containing a compound having Formula I as described above.
  • the present invention also relates to a method for treating glaucoma which involves administering an effective amount of a composition containing a compound having Formula I as described above.
  • the present invention relates to a variety of compounds which are useful according to the present invention. These compounds are represented by the following Formula I:
  • R 1 and R 2 are independently hydrogen or C 1-4 alkyl
  • R 3 is hydrogen or C 1-4 alkyl, or R 2 and R 3 together can complete a pyrrolidine or piperidine ring, which can be substituted with C 1- alkyl;
  • R 4 is hydrogen, halogen, or C 1-4 alkyl;
  • R 5 and R 6 are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxide, nitrile, or C 1-6 alkyl substituted with halogen;
  • R 8 is hydrogen, C 1-6 alkyl, or substituted C 1-6
  • R 9 is hydroxyl, C 1-6 alkoxy, NR 14 R 15 , C -6 alkyl, or substituted C 2-6 alkyl wherein the substituent is at least one of hydroxyl, C 1-6 alkoxy, NR 12 R 13 , CO 2 H, CO 2 C 1-6 alkyl, S(O) m NR 12 R 13 , halogen, and a heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo-4-yl, morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl, which can be unsubstituted or substituted with R 12 and R 13 are independently hydrogen, C 1-6 alkyl, or substituted C 2-6 alkyl wherein the substituent is at least one of hydroxyl, C 1-6 alkoxy, and halogen, or R 12 , R 13 , and the intervening nitrogen atom together can form a hetero
  • R 14 and R 15 are independently hydrogen, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, or substituted C 2-6 alkyl wherein the substituent is at least one of hydroxyl, C 1-6 alkoxy, halogen and a heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo- 4-yl, morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, which can be unsubstituted or substituted with C 1- alkyl, or R 14 ; R 15 , and the intervening nitrogen atom together can form a heterocyclic ring selected from mo holine, thiomorpholine, thiomorpholine 1 -oxide, thiomorpholine 1,1 -dioxide, azetidine, pyrrolidine, piperidine, piperazine, unsubstituted or substituted with C 1-4 alkyl or Ci
  • A is N or CH
  • X and Y are either N or C, provided that X and Y cannot be the same; and the dashed bonds denote a suitably appointed single and double bond.
  • Pharmaceutically acceptable salts and solvates, and prodrug forms of the compounds of Formula I are also part of the present invention. Certain compounds of Formula I can contain one or more chiral centers. The present invention contemplates all enantiomers, diastereomers, and mixtures thereof.
  • the total number of carbon atoms in a substituent group is indicated by the Cj.j prefix where the numbers i and j define the number of carbon atoms.
  • This definition includes straight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups.
  • a substituent may be present either singly or multiply when incorporated into the indicated structural unit.
  • the substituent halogen which means fluorine, chlorine, bromine, or iodine, would indicate that the unit to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.
  • alkoxy represents an alkyl group attached through an oxygen linkage.
  • alkyl includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms.
  • the alkyl groups maybe substituted with other groups, such as halogen, hydroxyl or alkoxy.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • aryl refers to carbon-based rings which are aromatic.
  • the rings may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
  • carbonyl represents a group that has a carbon atom that has a double bond to an oxygen atom.
  • cycloalkyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated.
  • the rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
  • halogen and "halo" represents fluoro, chloro, bromo, or iodo.
  • heteroaryl refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.
  • the heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
  • Preferred compounds of Formula I are: 1) (S)-2-(8,9-dmydro-9-me l-7H-[l,4]oxazino[2,3-g]indazol-l-yl)-l- methylethylaniine fumarate; 2) l-((S)-2-Amino ⁇ ro ⁇ yl)-l,9-d ⁇ ydro-7H-[l,4]oxazino[2,3- ⁇ ]fndazol-8-one hydrochloride;
  • the most preferred compound of Formula (I) is (S)-2-(8,9-dihydro-9-methyl-7H- [l,4]oxazmo[2,3-g]indazol-l-yl)-l-methylethylamine fumarate.
  • Compounds of Formula I can be prepared by using one of several synthetic procedures.
  • Pg denotes a suitable protective group to assure that a particular atom is not modified during the indicated chemical reaction.
  • Step B Benzyl (S)-2-[6-hydroxy-7-[(2-hydroxyethyl)methylamino]-lH-indazol-l- yl]-l-methylethylcarbamate
  • Step C Benzyl (S)-2-(8,9-dihydro-9-methyl-7H-[l,4]oxazino[2,3-g]indazol-l-yl)-l- methylethylcarbamate
  • Step D (S)-l-Methyl-2-(8,9-dihydro-9-methyl-7H-[l,4]oxazino[2,3- ]indazol-l- yl)ethylamine fumarate
  • Step A tert-Butyl (S)-[2-(6-hydroxyindazol-l-yl)-l-methylethylcarbamate
  • Step B tert-Butyl [2-(7-bromo-6-hydroxyindazol-l-yl)-l-methylethylcarbamate
  • N-bromosuccinimide 3.67 g, 20.6 mmol
  • the reaction mixture was evaporated and the residue was mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give an oil (8.12 g), which was used in the next step.
  • Step C tert-Butyl [2-(6-hydroxy-7-nitroindazol-l-yl)- 1-methyl-ethylcarbamate
  • a stirred solution of the product from Step B (1.63 g, 4.41 mmol) in a mixture of tetrahydrofuran (20 mL) and acetic acid (20 mL) was added sodium nitrite (0.304 g, 4.41 mmol) at ambient temperature. After 1 h another portion of sodium nitrite (0.304 g, 4.41 mmol) was added and the reaction was continued for additional 30 minutes.
  • the reaction mixture was poured into ice-water and extracted with ethyl acetate (3 x 80 mL). The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate till no bubbles formed and dried over magnesium sulfate. Evaporation gave an oil (1.74 g) that was used in the next reaction without further purification.
  • Step D tert-Butyl l-methyl-[2-(amino-6-hydroxyindazol-l-y ⁇ )]-l- methylethylcarbamate
  • methanol 60 mL
  • palladium-on-carbon 10%, 0.17 g
  • the reaction mixture was filtered and concentrated to give an oil (1.60 g): LC/MS (+APCI) m/z 307 (M+H).
  • Step E tert-Butyl [2-[7-(2-Chloroacetylamino)-6-hydroxyindazol-l-yl]-l-methyl ethylcarbamate
  • Step D The product from Step D (1.60 g) was dissolved in acetone (50 mL) and mixed with an aqueous solution of sodium bicarbonate (10 mL). The mixture was cooled (ice bath) and chloroacetyl chloride (0.351 mL, 4.41 mmol) was added with stirring. After 30 min the ice bath was removed and the reaction mixture was stirred for 1 h and extracted with ethyl acetate (3 x 50 ml).
  • Step F tert-Butyl 2-(8,9-dihydro-8-oxo-7H-[l,4]oxazino[2,3-g]indazol-l-yl)-l- methylethylcarbamate
  • Step E The product from Step E (0.42 g, 1.10 mmol) was dissolved in acetone (50 mL) and potassium carbonate (0.30 g, 2.17 mmol) was added; the suspension was heated at 50 ° C for 2 h, concentrated, and mixed with a saturated aqueous solution of sodium bicarbonate (50 mL).
  • Step G l-((S)-2-Aminopropyl)-l,9-dihydro-7H-[l,4]oxazino[2,3-g]indazol-8-one hydrochloride
  • Step B l-((S)-2-Aminopropyl)-9-methyl-l,9-dihydro-7H-[l,4]oxazino[2,3- g]indazol-8-one hydrochloride
  • the product from Step A (0.14 g, 0.39 mmol) was mixed with trifluoacetic acid
  • the compounds of the present invention can be used to lower and control IOP including IOP associated with normotension glaucoma, ocular hypertension, and so glaucoma in warm blooded animals including humans and other mammals. Since the treatment of glaucoma is preferably with compounds that do not enter the CNS, relatively polar compounds that are 5-HT 2 agonists are of particular interest.
  • the compounds are preferably formulated in pharmaceutical compositions which are preferably suitable for topical delivery to the eye of the patient.
  • the compounds of this invention, Formula I can be incorporated into various types of pharmaceutical compositions, such as ophthalmic formulations for delivery to
  • the compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye.
  • the compounds may be combined with ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophtiialmic solution formulations0 may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose,s polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not hrnited to, gellan and xanthan gum.
  • the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations mayo be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
  • the compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8.
  • the compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.25%) to 2% by weight.
  • 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to theo discretion of a skilled clinician.
  • the compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, /3-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), a.
  • ⁇ antagonists e.g., nipradolol
  • ⁇ agonists e.g.
  • iopidine and brimonidine miotics (e.g., pilocarpine and ⁇ inephrine), prostaglandin analogs (e.g., latanoprost, travoprost, unoprostone, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444, "hypotensive lipids" (e.g., bimatoprost and compounds set forth in 5,352,708), and neuroprotectants (e.g., compounds from U.S. Patent No.4,690,931, particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 60/203,350, and appropriate compounds from WO 94/13275, including memantine. ,
  • miotics e.g., pilocarpine and ⁇ inephrine
  • prostaglandin analogs e.g., la
  • the compounds of the present invention preferably provide increased chemical stability and preferably achieve the desired level of therapeutic activity which includes a lowering or controlling of IOP.
  • the compounds of the present invention can be used in controlling or lowering
  • the compounds of the present invention can be used to treat glaucoma in warm blooded animals, including humans, by administering an effective amount of the compound to a patient in need of such treatment to treat the glaucoma.
  • Pharmaceutically acceptable amounts of the compounds of the present invention will be readily understood by those skilled in the art to mean amounts sufficient to effect the desired therapy without toxicity or other deleterious effects on the patients' health. Examples of such amounts include without limitation those amounts shown in the Examples.
  • the assay mixture is incubated for 1 hour at 23°C in polypropylene tubes and the assays terminated by rapid vacuum filtration over Whatman GF/B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cold buffer.
  • Test compounds (at different concentrations) are substituted for methiothepin.
  • Filter-bound radioactivity is determined by scintillation spectrometry on a beta counter.
  • the data are analyzed using a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the compound affinity parameter.
  • the concentration of the compound needed to inhibit the [ 125 I]DOI binding by 50% of the maximum is termed the IC 50 or Kj value.
  • 5-HT 2 functional Assay [Ca 2+ ]j Mobilization
  • FLIPR Fluorescence Imaging Plate Reader
  • Rat vascular smooth muscle cells, A7r5 were grown in a normal media of DMEM / 10% FBS and 10 ⁇ g/mL gentamycin. Confluent cell monolayers were trypsinized, pelleted, and re-suspended in normal media. Cells were seeded in a 50 ⁇ L volume at a density of 20,000 cells / well in a black wall, 96-well tissue culture plate and grown for 2 days.
  • FLIPR Calcium Assay Kit dye was re-suspended in 50 mL of a FLIPR buffer consisting of Hank's Balanced Salt Solution (HBSS), 20 mM HEPES, and 2.5 mM probenecid, pH 7.4.
  • HBSS Hank's Balanced Salt Solution
  • HEPES Hydrophile
  • probenecid pH 7.4
  • Cells were loaded with the calcium-sensitive dye by addition of an equal volume (50 ⁇ L) to each well of the 96- well plate and incubated with dye for lh at 23°C.
  • test compounds were stored at 25 ⁇ M in 50% DMSO/50% Ethanol solvent. Compounds were diluted 1:50 in 20% DMSO/20% Ethanol.
  • the compound plate and cell plate were placed in the FLIPR instrument.
  • a signal test was performed to check the basal fluorescence signal from the dye-loaded cells and the uniformity of the signal across the plate.
  • the basal fluorescence was adjusted between 8000-12000 counts by modifying the exposure time, the camera F-stop, or the laser power.
  • Instrument settings for a typical assay were the following: laser power 0.3-0.6 W, camera F-stop F/2, and exposure time 0.4 sec.
  • An aliquot (25 ⁇ L) of the test compound was added to the existing 100 ⁇ L dye-loaded cells at a dispensing speed of 50 ⁇ L/sec.
  • Fluorescence data were collected in real-time at 1.0 sec intervals for the first 60 sees and at 6.0 sec intervals for an additional 120 sees. Responses were measured as peak fluorescence intensity minus basal and where appropriate were expressed as a percentage of a maximum 5-HT-induced response. When the compounds were tested as antagonists against 10 ⁇ M 5-HT, they were incubated with the cells for 15 minutes prior to the addition of 5-HT.
  • 5-HT 2 binding affinities and agonist potential can readily be determined.
  • topical ophthalmic formulations are useful according to the present invention administered 1-4 times per day according to the discretion of a skilled clinician.

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  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne des [1,4]oxazino[2,3-g]indazoles substitués permettant d'abaisser la pression intraoculaire et de traiter le glaucome.
PCT/US2004/041735 2003-12-15 2004-12-14 [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome Ceased WO2005058911A2 (fr)

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US60/529,507 2003-12-15

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Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7273889B2 (en) * 2002-09-25 2007-09-25 Innovative Drug Delivery Systems, Inc. NMDA receptor antagonist formulation with reduced neurotoxicity
US7476687B2 (en) * 2003-11-26 2009-01-13 Alcon, Inc. Substituted furo[2,3-g]indazoles for the treatment of glaucoma
US7338972B1 (en) * 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
US7129257B1 (en) * 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
TW200744567A (en) * 2005-09-23 2007-12-16 Alcon Inc Phenylethylamine analogs and their use for treating glaucoma
US20070293475A1 (en) * 2006-06-20 2007-12-20 Alcon Manufacturing Ltd. Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma
US20110293549A1 (en) 2009-02-03 2011-12-01 Athena Cosmetics, Inc. Composition, method and kit for enhancing hair
MX2022009050A (es) 2020-01-22 2022-10-27 Seelos Therapeutics Inc Reduccion de los efectos secundarios de los antagonistas de nmda.

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680931A (en) * 1980-03-20 1987-07-21 Jacobs Harvey C Constant speed control for positive displacement variable stroke hydraulic motor
FR2534580A1 (fr) 1982-10-13 1984-04-20 Synthelabo Derives de phenyl-1 piperidino-2 propanol, leur preparation, et medicaments qui les contiennent
US5151444B1 (en) 1987-09-18 1999-07-06 R Tech Ueno Ltd Ocular hypotensive agents
US5011846A (en) 1988-02-23 1991-04-30 Merrell Dow Pharmaceuticals Inc. Medicament compositions derived from quinolizine and quinolizinone and methods of use thereof
DE03014533T1 (de) 1988-09-06 2004-07-15 Pharmacia Ab Prostaglandinderivative zur Behandlung von Glaukom oder okuläre Hypertension
US5296504A (en) 1988-09-06 1994-03-22 Kabi Pharmacia Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
EP1293525A3 (fr) 1990-06-26 2005-09-07 AorTech Biomaterials Pty Ltd Compositons de polyuréthane ou polyuréthane-urée
US5578612A (en) 1990-10-15 1996-11-26 Pfizer Inc. Indole derivatives
DE69227458T2 (de) 1991-06-21 1999-04-29 Smith-Kline Beecham p.l.c., Brentford, Middlesex Tryptamin analoga, ihre herstellung und anwendung als 5-ht1-artige rezeptoren oder 5-ht2 rezeptor agonisten
GB9216380D0 (en) 1992-07-31 1992-09-16 Glaxo Group Ltd Medicaments
US5352708A (en) 1992-09-21 1994-10-04 Allergan, Inc. Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5922773A (en) 1992-12-04 1999-07-13 The Children's Medical Center Corp. Glaucoma treatment
US5290781A (en) 1993-01-05 1994-03-01 Iolab Corporation Ketaneserinol as an agent to reduce intraocular pressure
US5510383A (en) 1993-08-03 1996-04-23 Alcon Laboratories, Inc. Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension
TW270114B (fr) 1993-10-22 1996-02-11 Hoffmann La Roche
TW334423B (en) * 1993-10-22 1998-06-21 Hoffmann La Roche Tricyclic 1-aminoethylpyrrole-derivatives
US5538974A (en) 1994-01-27 1996-07-23 Senju Pharamceutical Co., Ltd. Ophthalmic composition for lowering intraocular pressure
DE69502539T2 (de) 1994-03-18 1998-10-01 Senju Pharma Co Sarpogrelat enthaltende opthalmologische Zubereitungen zur Senkung des intraokularen Druckes
TW403738B (en) 1994-08-12 2000-09-01 Hoffmann La Roche Tricyclic pyrazole derivatives
US5874477A (en) 1994-08-12 1999-02-23 The University Of Hawaii Method of treatment for malaria utilizing serotonin receptor ligands
US5998467A (en) 1995-10-25 1999-12-07 Mitsubishi Chemical Corporation Medicine for oculopathy
AU2340997A (en) 1996-03-27 1997-10-17 Merck & Co., Inc. A method for inhibiting clot formation
US5902815A (en) 1996-09-03 1999-05-11 Washington University Use of 5HT-2A serotonin agonists to prevent adverse effects of NMDA receptor hypofunction
WO1998018458A1 (fr) 1996-10-31 1998-05-07 Alcon Laboratories, Inc. Compositions ophtalmologiques contenant un agoniste du recepteur de la serotonine du type 5-ht1a et leur utilisation dans le traitement du glaucome
GB9700899D0 (en) 1997-01-17 1997-03-05 Smithkline Beecham Plc Novel treatment
AU727654B2 (en) * 1997-06-13 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Tricyclic pyrazole derivative
CA2325559A1 (fr) 1998-04-14 1999-10-21 Arena Pharmaceuticals, Inc. Formes non endogenes a activite constitutive de recepteurs humains de la serotonine et leurs petites molecules modulatrices
CA2332505A1 (fr) 1998-05-19 1999-11-25 Alcon Laboratories, Inc. Composes a affinite pour le recepteur de 5ht7 serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central
GB9819033D0 (en) 1998-09-01 1998-10-28 Cerebrus Ltd Chemical compounds VI
GB9819035D0 (en) 1998-09-01 1998-10-28 Cerebrus Res Ltd Chemical compounds VII
US6664286B1 (en) 1998-09-18 2003-12-16 Alcon Manufacturing, Ltd. Serotonergic 5ht2 agonists for treating glaucoma
JP2002532504A (ja) 1998-12-17 2002-10-02 アメリカン・ホーム・プロダクツ・コーポレイション ５−ｈｔ２ｃ作動薬である２，３，４，４ａ−テトラヒドロ−１ｈ−ピラジノ（１，２−ａ）キノキサリン−５（６ｈ）−オン誘導体
GB9902047D0 (en) 1999-01-29 1999-03-17 Cerebrus Ltd Chemical compounds XI
JP4916633B2 (ja) 1999-06-15 2012-04-18 ブリストル−マイヤーズ スクイブ ファーマ カンパニー 置換複素環縮合ガンマ−カルボリン
GB9918965D0 (en) * 1999-08-11 1999-10-13 Cerebrus Ltd Chemical compounds xxi
AU2042301A (en) 1999-12-03 2001-06-12 Alcon Universal Limited 1-aminoalkyl-1H-indoles for treating glaucoma
MXPA02009071A (es) 2000-03-17 2003-05-23 Alcon Inc Compuestos con actividad agonista de 5-ht 1a para tratar glaucoma..
WO2001070705A1 (fr) 2000-03-17 2001-09-27 Alcon, Inc. Derives de 2-acylaminobenzimidazole utilises pour traiter le glaucome
KR100499903B1 (ko) 2000-03-17 2005-07-07 아스텔라스세이야쿠 가부시키가이샤 안압 제어 및 녹내장 치료용 5ｈｔ2 효능제
DE60005566T2 (de) 2000-03-17 2004-07-29 Alcon, Inc. Pyranoindole zur glaukombehandlung
US6806285B1 (en) 2000-03-17 2004-10-19 Alcon, Inc. 5-Hydroxyl indole derivatives for treating glaucoma
PL365422A1 (en) 2000-03-17 2005-01-10 Alcon, Inc. 5-hydroxy indazole derivatives for treating glaucoma
AU2001216072A1 (en) 2000-03-17 2001-10-03 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
AU5256301A (en) 2000-04-28 2001-11-12 Yamanouchi Pharmaceutical Co., Ltd. Froindazole derivative
WO2001085152A2 (fr) 2000-05-10 2001-11-15 Alcon, Inc. R-eliprodil applique au traitement du glaucome
CN1393446B (zh) 2001-01-24 2010-06-16 永信药品工业股份有限公司 稠合吡唑化合物
EP1392658A4 (fr) 2001-06-01 2004-10-13 Alcon Inc Indazoles et indoles nouveaux fusionnes et leur utilisation dans le traitement de glaucomes
AU2002305732B2 (en) 2001-06-01 2007-02-01 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
MXPA03010806A (es) 2001-06-01 2004-11-22 Alcon Inc Nuevos analogos de arilaminopropano y su uso para el tratamiento de glaucoma.
US6884816B2 (en) 2001-08-31 2005-04-26 Alcon, Inc. Hydroxy substituted fused naphthyl-azoles and fused indeno-azoles and their use for the treatment of glaucoma
WO2003051291A2 (fr) 2001-12-14 2003-06-26 Alcon, Inc. Composes de 5-hydroxy-indole substitues destines au traitement du glaucome
JP2005511764A (ja) 2001-12-14 2005-04-28 アルコン，インコーポレイテッド 緑内障の処置のためのアミノアルキルベンゾフラン−５−オール化合物
TW593302B (en) 2001-12-20 2004-06-21 Alcon Inc Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
CA2486832A1 (fr) * 2002-05-30 2003-12-11 Alcon, Inc. Pyranoindazoles et leur utilisation pour le traitement du glaucome
CN1678302A (zh) 2002-08-30 2005-10-05 爱尔康公司 取代的5－苯并二氢吡喃－5－基－乙胺化合物及其在治疗青光眼中的用途
US20060106106A1 (en) 2002-09-24 2006-05-18 Glennon Richard A Beta-hydroxyphenylalkylamines and their use for treating glaucoma
CA2506204A1 (fr) 2002-12-13 2004-07-01 Alcon, Inc. Nouveaux analogues de benzopyranne et leur utilisation pour le traitement du glaucome
KR20050086927A (ko) 2002-12-23 2005-08-30 알콘, 인코퍼레이티드 1-알킬-3-아미노인다졸
RU2476677C2 (ru) 2007-07-31 2013-02-27 Сан Хуан Коул Компани Способ увеличения сопротивления потоку газа в шахте (варианты)

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US7268131B2 (en) 2007-09-11
US6989445B2 (en) 2006-01-24
AR046890A1 (es) 2005-12-28
US20050130960A1 (en) 2005-06-16
WO2005058911A3 (fr) 2005-08-25

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